Synapses represent key transduction machines that convert action potential-based signals into secreted chemical messages which in turn are converted back into postsynaptic electrical responses. Modulation of these processes is thought to underlie critical mechanisms of learning and memory, and dysfunction of synaptic communication is suspected to be central in a number of diseased states of brain function. It has long been known that the critical trigger for neurotransmitter release is the opening of voltage-gated calcium channels within the presynaptic terminal which in turn leads to the influx of calcium. The highly-non-linear relationship between calcium entry and exocytosis efficiency places the control of calcium channel function and abundance as a potent potential leverage point in sculpting synaptic strength. We recently demonstrated that expression of a calcium channel subunit, alpha2delta, is rate-limiting in determining how many calcium channels are present at nerve terminals in hippocampal neurons. Our work showed that it acts at 2 distinct molecular steps: it acts in a forward trafficking step to allow calcium channels to traffic to synapses and it acts locally at nerve terminals to allow channels to function at the presynaptic membrane. This second step requires the integrity of a predicted domain within alpha2delta that encodes a metal-ion-dependent adhesion site. In many other proteins this domain confers binding to an extracellular partner. We predict that proper alpha2delta function requires interaction with an as-yet-discovered binding partner on the synaptic surface. The goal of this proposal is to use biochemical approaches to identify this(ese) binding partner(s).